Abstract Targeted therapy development in head and neck squamous cell carcinoma (HNSCC) is challenging given the rarity of activating mutations. Additionally, HNSCC incidence is dramatically increasing related to human papillomavirus (HPV). We sought to develop an in vivo model derived from patients reflecting the evolving HNSCC epidemiologic landscape, and use it to identify new therapies. Primary and relapsed tumors from over 100 HNSCC patients, both HPV+ and HPV-, have been implanted on mice, giving rise to over 50 strains. Resulting xenografts were characterized by detecting key mutations, measuring protein expression by IHC and gene expression/pathway analysis by mRNA-sequencing. The genetic makeup of these tumors was consistent with the frequencies of TP53, PI3KCA, NOTCH1, and NOTCH2 mutations found in landmark genomic characterization of large HNSCC patient cohorts. Tumors maintained their original morphology, genetic profiles, and drug susceptibilities through serial passaging. Cancer cells deceive the host to create an advantageous microenvironment and evade immune surveillance. A limitation to studying human cancer is the limited availability of in vivo models with appropriate human stroma and immunity. To address this unmet need, we generated an allogeneic humanized mouse (aHM) model where HNSCC were implanted on NOD/SCID/IL2rg-/- (NSG) mice reconstituted with human hematopoietic stem cells (HSCs) and other precursors from an unrelated donor. In aHM, bone marrow-derived human immune and mesenchymal cells homed into the growing tumor and interacted with human cancer cells as they would in a patient, partially reversing the gene expression drift that occurs after tumor passage on immune compromised mice. Further work is aimed at improving upon this platform. In summary, we have developed a HNSCC model covering its clinical spectrum whose major genetic alterations and susceptibility to anticancer agents represent contemporary HNSCC. Then, we have generated an aHM model to enable immune biology and therapy exploration in HNSCC. These models will enable prospectively testing therapeutic-oriented hypotheses leading to enhanced precision medicine, especially in the field of immune therapy. Citation Format: Antonio Jimeno. PDX models in head and neck cancers: Present status and future application for immune-oriented biology and therapy development. abstract. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA14.